Background: Cardiovascular-kidney-metabolic syndrome (CKM) represents a multisystem condition involving obesity, diabetes, chronic kidney disease, and cardiovascular diseases. Frailty, as measured by the Frailty Index (FI), is linked to adverse outcomes, but its association with CKM severity and mortality remains unclear. This study aimed to evaluate the relationship between frailty status, CKM staging, and mortality risk. Methods: We analysed data from 19,407 adults aged ≥ 45 years from NHANES 1999–2018. Frailty status was assessed using a 49-item Frailty Index (FI) and categorised as robust (FI ≤ 0.08), pre-frail (0.08 < FI < 0.25), or frail (FI ≥ 0.25). CKM was staged from 1 to 4 based on established clinical criteria. Multinomial logistic regression assessed the association between frailty status and CKM staging. Cox proportional hazards models evaluated the associations between frailty status and all-cause, cardiovascular, and non-cardiovascular mortality among CKM patients. Results: A total of 19,407 participants (median [IQR] age: 63.00 [54.00–72.00] years, 50.77% male), with 19,089 CKM patients. Frail individuals exhibited significantly higher odds of being assigned to advanced CKM stages. Over a median follow-up of 8.4 years, 4794 participants died. Kaplan–Meier curves and restricted cubic spline analyses demonstrated a clear gradient in mortality risk across frailty categories. Compared with the robust group, pre-frail and frail individuals had significantly higher risks of all-cause (HR = 1.47 and 2.83, respectively), cardiovascular (HR = 1.71 and 3.78), and non-cardiovascular mortality (HR = 1.40 and 2.57). Conclusions: Frailty status demonstrated a significant association with CKM staging and mortality outcomes. Early identification of frailty may help guide risk stratification and inform tailored interventions for individuals with CKM.

The unclear pathogenesis of chronic itch originating from several systemic disorders poses challenges to clinical intervention. Recent studies recapitulate the spinal neurocircuits associated with neuroinflammation and synaptic plasticity responsible for pruriceptive sensations. The resolution of nociception and inflammation by Annexin 1 (ANXA1) has been identified. Given that pain and itch share many neural mechanisms, we employed two mice models of chronic itch to study the underlying targets and therapeutic potential of ANXA1, comprising allergic contact dermatitis-induced itch and cholestatic itch. Herein, we report that spinal expression of ANXA1 is down-regulated in mice with dermatitis-induced itch and cholestatic itch. Repetitive injections of ANXA1-derived peptide Ac2-26 (intrathecal, 10 μg) reduce itch-like scratching behaviors following dermatitis and cholestasis. Single exposure to Ac2-26 (intrathecal, 10 μg) alleviates the established itch phenotypes. Moreover, systemic delivery of Ac2-26 (intravenous, 100 μg) is effective against chronic dermatitis-induced itch and cholestatic itch. Strikingly, Ac2-26 therapy inhibits transferrin receptor 1 over-expression, iron accumulation, cytokine IL-17 release and the production of its receptor IL-17R, as well as astrocyte activation in the dorsal horn of spinal cord in mouse with dermatitis and cholestasis. Pharmacological intervention with iron chelator deferoxamine impairs chronic itch behaviors and spinal iron accumulation after dermatitis and cholestasis. Also, spinal IL-17/IL-17R neutralization attenuates chronic itch. Taken together, this current research indicates that ANXA1 protects against the beginning and maintenance of long-term dermatitis-induced itch and cholestatic itch, which may occur via the spinal suppression of IL-17-mediated neuroinflammation, astrocyte activation and iron overload.